The sigma-1 receptor is a unique non-opioid, non-PCP binding site that shares no homology with any mammalian proteins. In the brain, sigma-1 receptors are known to regulate the activity of diverse ion channels via protein-protein interactions. There is emerging evidence indicating that the activation of sigma-1 receptors promotes both neuronal differentiation and anti-apoptotic action (i.e. interferes with programmed cell death), potentially leading to cancer. Ligands for the sigma-1 receptor may constitute a new class of therapeutic drugs targeting an endoplasmic reticulum (ER) protein. Heretofore, ligands, particularly antagonists of the sigma-1 receptor have been scarce and poorly studied.
Interest in the sigma-1 receptor has increased since the recent discovery that the sigma-1 receptor may be a ligand-regulated mitochondrial membrane-associated ER chaperone, potentially leading to regulation of oxidative stress in mammalian cells, and that sigma ligands may have anti-tumorigenic activities. The sigma-1 receptor has been found to have promiscuous drug binding activity. A range of different pharmacological agents such as antipsychotics, haloperidol, Ca2+ channel antagonists such as verapamil, antidepressants such as fluoxetine, and CNS stimulants such as cocaine and methamphetamine, all bind to the sigma-1 receptor. See Hayashi et al., Expert Opin. Ther. Targets, 2008. 12(1): 45-58. Because of its promiscuity in drug binding activity, the sigma-1 receptor has been implicated in many different pathophysiological conditions including psychosis, drug addiction, retinal degeneration and cancer. Accordingly, new sigma ligands are needed to provide potential therapeutic agents for the treatment of these conditions and diseases.
Sigma-1 receptors are overexpressed in numerous tumor cell lines including breast cancer, small cell and non-small cell lung carcinoma, renal carcinoma, colon carcinoma, sarcoma, brain tumors, melanoma, glioblastoma, neuroblastoma, and prostate cancer. Because of this expression pattern, sigma-1 receptor ligands have potential in both imaging and treating cancer. A study showed that a putative antagonist of the sigma-1 receptor, rimcazole, was able to inhibit cellular proliferation and induce cell death. The mechanism underlying the inhibitory effect of sigma receptor drugs on tumor cell proliferation is unclear but has been shown to involve the activation of caspases 3 and 7 in the apoptotic pathway. Accordingly, the development of selective and/or high affinity sigma-1 receptor ligands is needed for diagnostic and therapeutic agent evaluation and development.